ProjectSummary/Abstract Thealarmingincreaseintheincidenceoftype2diabetesislargelyduetotheobesity epidemic.Thefailureofdietandexercisebasedstrategiestoreduceobesityhas renewedinterestinrestoringenergybalancethroughincreasedenergyexpenditurein adiposetissueviathermogenicpathways.However,themobilizationofenergyinwhite orbeigeadiposetissueinresponsetocoldexposureorsympatheticactivationremains poorlyunderstood.Basedonourpreliminarydata,weproposethatapreviously unrecognizedautocrinesignalingpathwayinvolvingsecretionofIl-6andactivationof Stat3maybeanimportantmodulatorofadipocyteenergyexpenditureinresponseto coldexposure.Thispathwayislikelyalsorelevantinotherphysiologicalcontextsin whichsympatheticsignalingintheadiposetissueisactivated.Theexperimentsoutlined inthisproposalaredesignedtoexploreandexpandinsightsintothisnovelsignaling pathwayanditsmetabolicconsequences.Thesestudieswillutilizeeithercoldexposure orb?-3adrenergicagonistinjectiontostimulatecatecholaminesignalinginadipocytes andactivatethisnovelsignalingaxis.Whilecoldexposureisaphysiologicalstimulus,b?- 3adrenergicagonistinjectionisapowerfultooltospecificallyinvestigatecatecholamine signalinginadipocytesinvivo,duetothespecificityoftheexpressionoftheb?-3 adrenergicreceptors.Aim1isdesignedtodeterminetheroleofIl-6inthemetabolic responsetocoldexposure.Whileaim2investigatesthespecificroleofadipocyteStat3 intheinductionofoxidativemetabolisminresponsetosympatheticactivationof adiposetissue.Finally,aim3willelucidatethemolecularmechanismofStat3actionin matureadipocyteslookingatbothtranscriptionfactoractivityandmitochondrial localization.Theworkproposedherelaysthegroundworkforfuturestudiesintohow thissignalingpathwayisaffectedbyobesity,anditspotentialastherapeutictargetin thefightagainstobesity.Thedataobtainedfromtheexperimentsproposedhereare anticipatedtosupportR01fundingforfuturestudies,therebypropellingtheapplicants careerasanindependentinvestigator.